Manufacture of tablet in a die utilizing powder blend containing water-containing material

ABSTRACT

The present invention features the present invention features a process for making a tablet by compacting a powder blend in a die platen to form a tablet shape, wherein the powder blend includes a pharmaceutically active agent and a water-containing material, and applying energy to the tablet shape for a sufficient period of time to heat the water-containing material within the tablet shape above its dehydration temperature to form the tablet.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority of the benefits of the filing of U.S.Provisional Application Ser. No. 61/245,315, filed Sep. 24, 2009, U.S.Provisional Application Ser. No. 61/255,582, filed Oct. 28, 2009, U.S.Provisional Application Ser. No. 61/314,629, filed Mar. 17, 2010, andU.S. Provisional Application Ser. No. 61/358,167, filed Jun. 24, 2010.The complete disclosures of the aforementioned related U.S. patentapplications are hereby incorporated herein by reference for allpurposes.

BACKGROUND OF THE INVENTION

Pharmaceuticals intended for oral administration are typically providedin tablet form. Tablets are swallowed whole, chewed in the mouth, ordisintegrated in the oral cavity. Soft tablets that either are chewed ordissolve in the mouth are often employed in the administration ofpharmaceuticals where it is impractical to provide a tablet forswallowing whole. With chewable tablets, the act of chewing helps tobreak up the tablet particles as the tablet disintegrates and mayincrease the rate of absorption by the digestive tract. Soft tablets arealso advantageous where it is desirable to make a pharmaceuticallyactive agent available topically in the mouth or throat for both localeffects and/or systemic absorption. Soft tablets are also utilized toimprove drug administration in pediatric and geriatric patients. Softtablets designed to disintegrate in the mouth prior to swallowing areparticularly useful for improving compliance of pediatric patients.

Generally, soft tablets are made by compaction of a blend of powderedingredients and typically include a pharmaceutically active agent,flavoring, and/or binders. The powder blend is typically fed into thecavity of a die of a tablet press and a tablet is formed by applyingpressure. Hardness of the resulting tablet is a direct function of thecompaction pressure employed and the compatibility of the ingredients inthe formulation. A softer tablet, having an easier bite-through, may beprepared by employing reduced compaction pressures. The resulting tabletis softer, but also more fragile, brittle, and easily chipped anddisadvantageously can involve complex and costly processing steps.Examples of soft tablets designed to disintegrate in the mouth withoutchewing are disclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878,6,589,554, and 6,224,905.

There is a need for aesthetically pleasing chewable and orallydisintegrating tablets that utilizes compression-based tabletingmachines typically used to produce high density, hard swallowabletablets. When used at low compression forces, these machines typicallyproduce highly friable tablets, which are not sufficiently stable duringpackaging, shipping, and storage. The present invention relates to thediscovery of a process for making tablets, such as chewable or orallydisintegrating tablets, by heating (e.g., radiofrequency heating) awater-containing material that can utilize high speed tabletingmachines.

SUMMARY OF THE INVENTION

In one aspect, the present invention features a process for making atablet by compacting a powder blend in a die platen to form a tabletshape, wherein the powder blend includes a pharmaceutically active agentand a water-containing material, and applying energy to the tablet shapefor a sufficient period of time to heat the water-containing materialwithin the tablet shape above its dehydration temperature to form thetablet. In one embodiment, the energy is radiofrequency (“RF”) energy.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-F are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 4 a from powder blend 4within die platen 2.

FIGS. 2A-H are cross-section, side views of an embodiment of theinvention showing the manufacture of a bilayer tablet 12 from powderblends 10 and 11 within die platen 2.

FIGS. 3A-F are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 40 containing preformedinserts 30 and 31 from powder blend 20 within die platen 2.

FIGS. 4A and 4B are a perspective view of a rotary indexing machine 195.

FIGS. 5A and 5B are top views of the rotary indexing machine 195 in thedwell position.

FIGS. 6A and 6B are section views of the lower forming tool assembly 110in the start position of the manufacturing cycle.

FIG. 7 is a section view through the RF station rotary indexing machine195 prior to compacting powder blend 101.

FIG. 8 is a section view through the RF station rotary indexing machine195 prior showing the manufacture of tablets 101 a.

FIG. 9 is a section view through tablet ejection station 160 beforetablets 101 a have been ejected.

FIG. 10 is a section view through tablet ejection station 160 aftertablets 101 a have been ejected into blister 190.

FIGS. 11A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIGS. 12A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIG. 13A is a cross section of forming tools having a wave-shapedsurface.

FIG. 13B is a perspective view of forming tools having a wave-shapedsurface.

FIG. 14 is a cross section of forming tools having protrusions at thesurface.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments can be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified.

As discussed above, in one aspect, the present invention features aprocess for making a tablet by compacting a powder blend in a die platento form a tablet shape, wherein the powder blend includes apharmaceutically active agent and a water-containing material, andapplying energy to the tablet shape for a sufficient period of time toheat the water-containing material within the tablet shape above itsdehydration temperature to form the tablet.

Powder Blend

As discussed above, the tablet is manufactured by compacting a powderblend containing a pharmaceutically active agent (as discussed herein),a water-containing material (as discussed herein), and optionally apharmaceutically-acceptable carrier. The carrier contains one or moresuitable excipients for the formulation of tablets. Examples of suitableexcipients include, but are not limited to, fillers, adsorbents,disintegrants, lubricants, glidants, sweeteners, superdisintegrants,flavor and aroma agents, antioxidants, preservatives, texture enhancers,and mixtures thereof. One or more of the above ingredients may bepresent on the same particle of the powder blend.

Suitable fillers include, but are not limited to, carbohydrates (asdiscussed herein) and water insoluble plastically deforming materials(e.g., microcrystalline cellulose or other cellulosic derivatives), andmixtures thereof.

Suitable adsorbents include, but are not limited to, water-insolubleadsorbents such as dicalcium phosphate, tricalcium phosphate, silicifiedmicrocrystalline cellulose (e.g., such as distributed under the PROSOLVbrand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesiumaluminometasilicate (e.g., such as distributed under the NEUSILIN brand(Fuji Chemical Industries (USA) Inc., Robbinsville, N.J.)), clays,silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum,and mixtures thereof.

Suitable disintegrants include, but are not limited to, sodium starchglycolate, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethylcellulose, starches, microcrystalline cellulose, andmixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicondioxide.

Examples of sweeteners include, but are not limited to, synthetic ornatural sugars; artificial sweeteners such as saccharin, sodiumsaccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose,dihydrochalcone, alitame, miraculin, monellin, and stevside; sugaralcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, andxylitol; sugars extracted from sugar cane and sugar beet (sucrose),dextrose (also called glucose), fructose (also called laevulose), andlactose (also called milk sugar); isomalt, salts thereof, and mixturesthereof.

Examples of superdisintegrants include, but are not limited to,croscarmellose sodium, sodium starch glycolate and cross-linked povidone(crospovidone). In one embodiment the tablet contains up to about 5% byweight of such superdisintegrant.

Examples of flavors and aromatics include, but are not limited to,essential oils including distillations, solvent extractions, or coldexpressions of chopped flowers, leaves, peel or pulped whole fruitcontaining mixtures of alcohols, esters, aldehydes and lactones;essences including either diluted solutions of essential oils, ormixtures of synthetic chemicals blended to match the natural flavor ofthe fruit (e.g., strawberry, raspberry and black currant); artificialand natural flavors of brews and liquors, e.g., cognac, whisky, rum,gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint;fruit juices including expelled juice from washed, scrubbed fruits suchas lemon, orange, and lime; spear mint, pepper mint, wintergreen,cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseedsnuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts),almonds, raisins; and powder, flour, or vegetable material partsincluding tobacco plant parts, e.g., genus Nicotiana, in amounts notcontributing significantly to the level of nicotine, and ginger.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.

Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

Examples of texture enhancers include, but are not limited to, pectin,polyethylene oxide, and carrageenan, and mixtures thereof. In oneembodiment, texture enhancers are used at levels of from about 0.1% toabout 10% percent by weight.

In one embodiment of the invention, the powder blend has an averageparticle size of less than 500 microns, such as from about 50 microns toabout 500 microns, such as from about 50 microns and 300 microns.Particles in this size range are particularly useful for directcompacting processes.

In one embodiment of the invention, the tablet may be a made from apowder blend that is substantially free of hydrated polymers. As usedherein, what is meant by “substantially free” is less than 5%, such asless than 1%, such as less than 0.1%, such as completely free (e.g.,0%). Such a composition is advantageous for maintaining an immediaterelease dissolution profile, minimizing processing and material costs,and providing for optimal physical and chemical stability of the tablet.

In one embodiment, powder blend/tablet is substantially free of directlycompressible water insoluble fillers. Water insoluble fillers includebut are not limited to microcrystalline cellulose, directly compressiblemicrocrystalline cellulose, celluloses, water insoluble celluloses,starch, cornstarch and modified starches. As described in thisembodiment, substantially free is less than 2 percent, e.g. less than 1percent or none.

Water-Containing Material

The powder blend/tablet of the present invention includes at least onewater-containing material. Examples of water-containing materialsinclude, but are not limited to, materials wherein the water ischemically bound to the material (e.g., a hydrate salt or hydratedsugar), materials wherein the water is adsorbed or absorbed to thematerial (e.g., porous material such a silicas and microsponges), andmaterials that have water encapsulated therein (e.g., liquid filledcapsules).

In one embodiment, the powder blend/tablet contains at least onehydrated salt. Examples of hydrated salts include, but are not limitedto, sodium sulfate hydrate, sodium carbonate hydrate, calcium chloridehydrate, sodium hydrogen phosphate hydrate, and mixtures thereof. In oneembodiment, the hydrated salt has molecular weight from about 150 toabout 400 Daltons, such as from about 200 to about 350 Daltons.

In one embodiment, the powder blend/tablet contains at least onehydrated sugar. Examples of hydrated sugars include, but are not limitedto, dextrose monohydrate. In one embodiment, the powder blend/tabletcontains at least one material wherein the water is adsorbed or absorbedto the material. Examples of such materials include, but are not limitedto, fumed silicas; colloidal silicas such as colloidal silicon dioxide;silicates such as calcium silicate, aluminum silicate, magnesiumaluminum metasilicate (such as NEUSILIN, US-2 from Fuji Chemical Ltd),and magnesium silicate; clays; zeolites; and veegum.

In one embodiment, the powder blend/tablet contains at least one liquidfilled capsule. In a further embodiment, the water is released from thecapsule upon rupture, wherein such rupture is caused by the addition ofenergy.

The water-containing material(s) may be present at level of about 0.01percent to about 70 percent of the powder blend/tablet, such as fromabout 1 percent to about 50 percent, such as from about 1 percent toabout 30 percent, such as from about 2 per cent to about 10 percent ofthe powder blend/tablet.

Carbohydrate

In one embodiment, the powder blend/tablet contains at least onecarbohydrate. The carbohydrate can (i) upon contact with the waterreleased from the water-containing material, contribute to binding thepowder blend into a tablet, (ii) enhance the dissolvability and mouthfeel of the tablet, (iii) aid in distributing the water-containingmaterial across a broader surface area, and (iv) diluting and cushioningthe pharmaceutically active agent. Examples of carbohydrates include,but are not limited to, water-soluble compressible carbohydrates such assugars (e.g., dextrose, sucrose, maltose, isomalt, and lactose),starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol,maltitol, erythritol, lactitol, and xylitol), and starch hydrolysates(e.g., dextrins, and maltodextrins).

The carbohydrate(s) may be present at level of about 5 percent to about95 percent of the powder blend/tablet, such as from about 20 percent toabout 90 percent or from about 40 percent to about 80 percent of thepowder blend/tablet. In one embodiment, the powder blend/tablet issubstantially free (e.g., completely free) of a water-reacting bindingmaterial or meltable binder, such that the carbohydrate acts to fuse thedosage form upon the addition of the energy (e.g., RF energy). In thisembodiment substantially free is defined as less than 0.1 percent, suchas 0%.

Water-Reacting Binding Material

In one embodiment, the powder blend/tablet of the present inventionincludes at least one water-reacting binding material. What is meant bya water-reacting binding material is a material that will react orhydrate upon contact with water (e.g. released from the water containingmaterial upon the addition of the energy) and assist in binding thepowder blend into a tablet. Examples of such materials include, but arenot limited to, hydrating polymers and hydrocolloids. Suitable hydratingpolymers include, but are not limited to starch, modified starch,methylcellulose, hydroxypropylcellulose, and hydroxypropylcellulose.Suitable hydrocolloids include, but are not limited to, gelatin, gellangum, carrageenan, and pectin.

Meltable Binder

In one embodiment, the powder blend/tablet of the present inventionincludes at least one meltable binder. In one embodiment, the meltablebinder has a melting point of from about 40° C. to about 140° C., suchas from about 55° C. to about 100° C. The softening or melting of themeltable binder(s) results in the sintering of the tablet shape throughthe binding of the softened or melted binder with the pharmaceuticallyactive agent and/or other ingredients within the compacted powder blend.

In one embodiment, the meltable binder is a RF-meltable binder. What ismeant by an RF-meltable binder is a solid binder that can be softened ormelted upon exposure to RF energy. The RF-meltable binder typically ispolar and has the capability to re-harden or resolidify upon cooling.

In one embodiment, the meltable binder is not a RF-meltable binder. Insuch embodiment, the powder blend contains an excipient that heats uponexposure to RF energy (e.g., a polar excipient), such that the resultingheat from is able to soften or melt the meltable binder. Examples ofsuch excipients include, but are not limited to, polar liquids such aswater and glycerin; powdered metals and metal salts such as powderediron, sodium chloride, aluminum hydroxide, and magnesium hydroxide;stearic acid; and sodium stearate.

Examples of suitable meltable binders include: fats such as cocoabutter, hydrogenated vegetable oil such as palm kernel oil, cottonseedoil, sunflower oil, and soybean oil; mono, di, and triglycerides;phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermacetiwax, beeswax, candelilla wax, shellac wax, microcrystalline wax, andparaffin wax; water soluble polymers such as polyethylene glycol,polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides; polyethylene oxides; and sucroseesters.

In one embodiment, the meltable binder is a RF-meltable binder, and theRF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000. Aparticularly preferred RF-meltable binder is PEG having at least 95% byweight of the PEG particles less than 100 microns (as measured byconventional means such as light or laser scattering or sieve analysis)and a molecular weight between 3000 and 8000 Daltons.

In one embodiment, the meltable binder is hydrated. In a furtherembodiment, upon addition of the energy the meltable binder releases thewater into the powder blend. In one embodiment, the hydrated meltablebinder includes up to 60 percent, such as up to about 50 percent, byweight of water.

The meltable binder(s) may be present at level of about 0.01 percent toabout 70 percent of the powder blend/tablet, such as from about 1percent to about 50 percent, such as from about 10 percent to about 30percent of the powder blend/tablet.

Pharmaceutically Active Agent

The powder blend/tablet of the present invention includes at least onepharmaceutically active agent. What is meant by a “pharmaceuticallyactive agent” is an agent (e.g., a compound) that is permitted orapproved by the U.S. Food and Drug Administration, European MedicinesAgency, or any successor entity thereof, for the oral treatment of acondition or disease. Suitable pharmaceutically active agents include,but are not limited to, analgesics, anti-inflammatory agents,antipyretics, antihistamines, antibiotics (e.g., antibacterial,antiviral, and antifungal agents), antidepressants, antidiabetic agents,antispasmodics, appetite suppressants, bronchodilators, cardiovasculartreating agents (e.g., statins), central nervous system treating agents,cough suppressants, decongestants, diuretics, expectorants,gastrointestinal treating agents, anesthetics, mucolytics, musclerelaxants, osteoporosis treating agents, stimulants, nicotine, andsedatives.

Examples of suitable gastrointestinal treating agents include, but arenot limited to: antacids such as aluminum-containing pharmaceuticallyactive agents (e.g., aluminum carbonate, aluminum hydroxide,dihydroxyaluminum sodium carbonate, and aluminum phosphate),bicarbonate-containing pharmaceutically active agents,bismuth-containing pharmaceutically active agents (e.g., bismuthaluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate,and bismuth subnitrate), calcium-containing pharmaceutically activeagents (e.g., calcium carbonate), glycine, magnesium-containingpharmaceutically active agents (e.g., magaldrate, magnesiumaluminosilicates, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, and magnesium trisilicate),phosphate-containing pharmaceutically active agents (e.g., aluminumphosphate and calcium phosphate), potassium-containing pharmaceuticallyactive agents (e.g., potassium bicarbonate), sodium-containingpharmaceutically active agents (e.g., sodium bicarbonate), andsilicates; laxatives such as stool softeners (e.g., docusate) andstimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such asfamotidine, ranitidine, cimetadine, and nizatidine; proton pumpinhibitors such as omeprazole, dextansoprazole, esomeprazole,pantoprazole, rabeprazole, and lansoprazole; gastrointestinalcytoprotectives, such as sucraflate and misoprostol; gastrointestinalprokinetics such as prucalopride; antibiotics for H. pylori, such asclarithromycin, amoxicillin, tetracycline, and metronidazole;antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate,and loperamide; glycopyrrolate; analgesics, such as mesalamine;antiemetics such as ondansetron, cyclizine, diphenyhydroamine,dimenhydrinate, meclizine, promethazine, and hydroxyzine; probioticbacteria including but not limited to lactobacilli; lactase;racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g.,dimethicone and simethicone, including those disclosed in U.S. Pat. Nos.4,906,478, 5,275,822, and 6,103,260); isomers thereof; andpharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyreticsinclude, but are not limited to, non-steroidal anti-inflammatory drugs(NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen,ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen)and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylicacid; acetic acid derivatives such as indomethacin, diclofenac,sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid,meclofenamic acid, and flufenamic acid; biphenylcarbodylic acidderivatives such as diflunisal and flufenisal; and oxicams such aspiroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; andpharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants, include, but are notlimited to, bromopheniramine, chlorcyclizine, dexbrompheniramine,bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine,pripolidine, ephedrine, phenylephrine, pseudoephedrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine,naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine,clemastine, acrivastine, promethazine, oxomemazine, mequitazine,buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide,xylomeazoline, loratadine, desloratadine, and cetirizine; isomersthereof; and pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include, but are notlimited to, diphenhydramine, dextromethorphan, noscapine, clophedianol,menthol, benzonatate, ethylmorphone, codeine, acetylcysteine,carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, andguaifenesin; isomers thereof; and pharmaceutically acceptable salts andprodrugs thereof.

Examples of muscle relaxants include, but are not limited to,cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, andmethocarbamol; isomers thereof; and pharmaceutically acceptable saltsand prodrugs thereof.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to sleep aids such asantihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of appetite suppressants include, but are not limited to,phenylpropanolamine, phentermine, and diethylcathinone, andpharmaceutically acceptable salts and prodrugs thereof

Examples of anesthetics (e.g., for the treatment of sore throat)include, but are not limited to dyclonine, benzocaine, and pectin andpharmaceutically acceptable salts and prodrugs thereof.

Examples of suitable statins include but are not limited to atorvastin,rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin,pravastatin and pharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent included within thetablet is selected from phenylephrine, dextromethorphan,pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine,ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calciumcarbonate, simethicone, chlorpheniramine, methocarbomal, chlophedianol,ascorbic acid, pectin, dyclonine, benzocaine and menthol, andpharmaceutically acceptable salts and prodrugs thereof.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of pharmaceutically acceptablesalts, such as acidic/anionic or basic/cationic salts. Pharmaceuticallyacceptable acidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphospate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide. Pharmaceutically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of prodrugs of thepharmaceutically active agents. In general, such prodrugs will befunctional derivatives of the pharmaceutically active agent, which arereadily convertible in vivo into the required pharmaceutically activeagent. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, theinvention provides the esters, amides, and other protected orderivatized forms of the described compounds.

Where the pharmaceutically active agents according to this inventionhave at least one chiral center, they may accordingly exist asenantiomers. Where the pharmaceutically active agents possess two ormore chiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore, someof the crystalline forms for the pharmaceutically active agents mayexist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the pharmaceutically activeagents may form solvates with water (e.g., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In one embodiment, the pharmaceutically active agent or agents arepresent in the tablet in a therapeutically effective amount, which is anamount that produces the desired therapeutic response upon oraladministration and can be readily determined by one skilled in the art.In determining such amounts, the particular pharmaceutically activeagent being administered, the bioavailability characteristics of thepharmaceutically active agent, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.

The pharmaceutically active agent may be present in various forms. Forexample, the pharmaceutically active agent may be dispersed at themolecular level, e.g. melted, within the tablet, or may be in the formof particles, which in turn may be coated or uncoated. If thepharmaceutically active agent is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 to about 2000 microns. In one embodiment, such particlesare crystals having an average particle size of from about 1 to about300 microns. In another embodiment, the particles are granules orpellets having an average particle size of from about 50 to about 2000microns, such as from about 50 to about 1000 microns, such as from about100 to about 800 microns.

The pharmaceutically active agent may be present in pure crystal form orin a granulated form prior to the addition of the taste masking coating.Granulation techniques may be used to improve the flow characteristicsor particle size of the pharmaceutically active agents to make it moresuitable for compaction or subsequent coating. Suitable binders formaking the granulation include but are not limited to starch,polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose,and hydroxypropylcellulose. The particles including pharmaceuticallyactive agent(s) may be made by cogranulating the pharmaceutically activeagent(s) with suitable substrate particles via any of the granulationmethods known in the art. Examples of such granulation method include,but are not limited to, high sheer wet granulation and fluid bedgranulation such as rotary fluid bed granulation.

If the pharmaceutically active agent has an objectionable taste, thepharmaceutically active agent may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked pharmaceutically active agents may also be employed. For example,acetaminophen particles, which are encapsulated with ethylcellulose orother polymers by a coacervation process, may be used in the presentinvention. Coacervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio) or from CircaInc. (Dayton, Ohio).

In one embodiment, the tablet incorporates modified release coatedparticles (e.g., particles containing at least one pharmaceuticallyactive agent that convey modified release properties of such agent). Asused herein, “modified release” shall apply to the altered release ordissolution of the active agent in a dissolution medium, such asgastrointestinal fluids. Types of modified release include, but are notlimited to, sustained release or delayed release. In general, modifiedrelease tablets are formulated to make the active agents(s) availableover an extended period of time after ingestion, which thereby allowsfor a reduction in dosing frequency compared to the dosing of the sameactive agent(s) in a conventional tablet. Modified release tablets alsopermit the use of active agent combinations wherein the duration of onepharmaceutically active agent may differ from the duration of anotherpharmaceutically active agent. In one embodiment the tablet contains onepharmaceutically active agent that is released in an immediate releasemanner and an additional active agent or a second portion of the sameactive agent as the first that is modified release.

Examples of swellable, erodible hydrophilic materials for use as arelease modifying excipient for use in the modified release coatinginclude water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, and gelling starches. Examples of water swellable cellulosederivatives include sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examplesof polyalkylene glycols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkylene oxides include poly (ethyleneoxide). Examples of acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, andhigh-molecular weight cross-linked acrylic acid homopolymers andcopolymers.

Suitable pH-dependent polymers for use as release-modifying excipientsfor use in the modified release coating include: enteric cellulosederivatives such as hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, and cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as polyvinylacetate phthalate, cellulose acetatephthalate, and acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2 (available fromRohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylicacid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH underthe tradename EUDRAGIT L).

In one embodiment the pharmaceutically active agent is coated with acombination of a water insoluble film forming polymer (such as but notlimited to cellulose acetate or ethylcellulose) and a water solublepolymer (such as but not limited to povidone, polymethacrylicco-polymers such as those sold under the tradename Eudragit E-100 fromRohm America, and hydroxypropylcellulose). In this embodiment, the ratioof water insoluble film forming polymer to water soluble polymer is fromabout 50 to about 95 percent of water insoluble polymer and from about 5to about 50 percent of water soluble polymer, and the weight percent ofthe coating by weight of the coated taste-masked particle is from about5 percent to about 40 percent. In one embodiment, the coating which isused in the coated particle of the pharmaceutically active agent issubstantially free of a material (such as polyethylene glycol) whichmelts below 85° C., in order to prevent damage to the integrity of thecoating during the RF heating step. In one embodiment, one or morepharmaceutically active agents or a portion of the pharmaceuticallyactive agent may be bound to an ion exchange resin for the purposes oftaste-masking the pharmaceutically active agent or delivering the activein a modified release manner

In one embodiment, the pharmaceutically active agent is capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In one embodiment, the dissolutioncharacteristics of the pharmaceutically active agent within the tabletmeets USP specifications for immediate release tablets including thepharmaceutically active agent. For example, for acetaminophen tablets,USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the acetaminophen contained in thetablet is released there from within 30 minutes after dosing, and foribuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer,using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofencontained in the tablet is released there from within 60 minutes afterdosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In anotherembodiment, the dissolution characteristics of the pharmaceuticallyactive agent are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like.

In one embodiment, the particle size of the pharmaceutically activeagent causes more void spaces to be present in the tablet, wherein ahigher particle size of the pharmaceutically active agent subsequentlyrequires a lower level of the water-containing material. In oneembodiment, the mean particle size of the carbohydrate is greater than100 microns, the pharmaceutically active agent or coatedpharmaceutically active agent(s) is greater than 50% by weight of thepowder blend/tablet and the water-containing material is from about 2%to about 30% by weight of the powder blend/tablet. In one embodiment,wherein the mean particle size of the powder blend is from about 100microns and about 300 microns, then the water-containing material isfrom about 2% to about 15% percent by weight of the powder blend/tablet.

The melting point of the pharmaceutically active agent can have animpact on the temperature used during the heating step and the type ofthe water-containing material used. In one embodiment, the dehydrationtemperature of the water-containing material is less than the meltingpoint of the pharmaceutically active agent. In another embodiment, themelting point of the pharmaceutically active agent is the same or lowerthan the dehydration temperature of the water-containing material. Inone embodiment, the heating temperature is above the melting dehydrationtemperature of the water-containing material and below the melting pointof the pharmaceutically active agent. In one embodiment whereinibuprofen is the pharmaceutically active agent, the water-containingmaterial is heated from about 30° C. to about 60° C. In one embodiment,the pharmaceutically active agent is the water-reacting bindingmaterial.

In one embodiment, the pharmaceutically active agent is in the form of aparticle that is coated with the water-reacting binding material.

The susceptibility to RF energy of the pharmaceutically active agent(e.g., to melt or degrade) can have an impact on the type of energyand/or temperature used during the heating step as well as the type ofthe water-containing compound used.

In one embodiment, the processing of the tablet is free of a wet or hotmelt granulation step. In this embodiment, the materials are directlyblended prior to the addition of heat. In one embodiment, the materialsare directly blended and compressed prior to the addition of heat.

Manufacture of Tablet Shape

In one embodiment, the powder blend is fed into the tablet die of anapparatus that applies pressure to form the tablet shape (e.g., by lightcompaction such as tamping). Any suitable compacting apparatus may beused, including, but not limited to, a conventional unitary or rotarytablet press. In one embodiment, the tablet shape may be formed bycompaction using a rotary tablet press (e.g., such as those commerciallyavailable from Fette America Inc., Rockaway, N.J. or Manesty MachinesLTD, Liverpool, UK). In one embodiment, the tablet shape is heated afterit is removed from the tablet press. In another embodiment, the tabletshape is heated within the tablet press.

In one embodiment, to obtain desired attribute of an orallydisintegrating tablet, the tablet's construction may be highly porous,use a minimal amount of binder, and/or have a low density. Such tablets,therefore, are somewhat fragile and soft. In a preferred embodiment, aminimum of tamping/compaction force is desired to achieve the orallydisintegrating property (low density). Experiments have determined thatlow force compaction without application of RF energy produced veryfragile tablets that could not withstand the forces of material handlingrequired in manufacturing.

In most thermodynamic processes or machines, the heat source and theheat sink are two distinct machines or steps requiring material to betransferred from one apparatus to the other. In the manufacture of thetablets of the present invention, the energy must be added to the tabletto achieve the binding effect and then must be removed from the productto solidify and strengthen it for its final handling packaging and use.One of the unique and unanticipated attributes of one embodiment of themanufacturing process of the present invention is that heat source andheat sink are part of the same apparatus. In fact in early experimentsthe metallic forming tool (e.g., a die punch) which was at roomtemperature removed so much heat from the treated tablet shape (due toits high thermal conductivity) that the surface of the resulting tabletwas unacceptable due to the fact that uniform melting within the powderblend had not taken place. The resulting tablet had a well formed core,but the surface was loose unbound and poorly formed powder that did notadhere to the rest of the tablet. To correct for this thermal loss, inone embodiment, heat is added to the forming tools to achieve propersintering at the surface as well as at the center of the tablet.

To exploit this unique thermal effect, powder blends can also be chosenfor their thermal properties and thermal conductivity and specific heatsuch that the powder blend particles themselves become heat sinks. In atypical ODT formulation the binders may compose less than 10% of themixture. The remaining 90% of the materials act as a heat sink thatquickly removes heat once the energy (e.g., RF energy) is removed. Thedesirable result of this is that the total process time can be just afew seconds and that the tablet does not need to be transferred from thedie platen during the critical tamping and heating process. The dieplaten can function then as a material handling apparatus as well as athermal forming tool. This is particularly advantageous for successfulmanufacture of fragile orally disintegrating tablets.

In one embodiment, the compaction step (e.g., tamping) which occursprior to the addition of the energy (e.g., RF energy) utilizes acompaction force which is less than the force required to compress achewable or swallowable tablet. In one embodiment, the compaction forceis less than about 1000 pounds per square inch (e.g., less than about500 pounds per square inch, such as less than 200 pounds per squareinch, such as less than 50 pounds per square inch). In one embodiment,the energy is applied while the powder blend is under such force.

In one embodiment, the compaction step occurs in an indexed manner,where one set of tablets are compacted simultaneously, before rotatingto another indexing station. In one embodiment, the compaction stepoccurs at a single indexing station and the application of energy (e.g.,RF energy) occurs at a separate indexing station. In another embodiment,a third indexing station is present wherein the ejection of the tabletor multiple tablets occurs, wherein the lower forming tool is raised upthrough and up to the surface of the die. In another embodiment thecompaction step is performed through the addition of air pressure orhydraulic cylinder to the top of the upper forming tools. In oneembodiment multiple tablets are ejected simultaneously and separatedfrom the surface of the indexing station and removed via a take-off bar.

In another embodiment, the tablet shape may be prepared by thecompaction methods and apparatus described in United States PatentApplication Publication No. 20040156902. Specifically, the tablet shapemay be made using a rotary compression module including a fill zone,insertion zone, compression zone, ejection zone, and purge zone in asingle apparatus having a double row die construction. The dies of thecompression module may then be filled using the assistance of a vacuum,with filters located in or near each die. The purge zone of thecompression module includes an optional powder blend recovery system torecover excess powder blend from the filters and return the powder blendto the dies. In one embodiment the energy source (e.g., RF energysource) is projected through the die table of a rotary press into theappropriate electrode within the forming tool or the forming cavity. Inone embodiment the die table is constructed of non-conductive material.

In another embodiment, a portion of the tablet shape may be prepared bya wet-granulation method, in which the excipients and a solution ordispersion of a wet binder (e.g., an aqueous cooked starch paste orsolution of polyvinyl pyrrolidone) are mixed and granulated. Suitableapparatus for wet granulation include low shear mixers (e.g., planetarymixers), high shear mixers, and fluid beds (including rotary fluidbeds). The resulting granulated material may then be dried, andoptionally dry-blended with further ingredients (e.g., excipients suchas, for example, the water-containing compound described in theinvention herein, lubricants, colorants, and the like). The final dryblend is then suitable for compaction by the methods described herein.Methods for direct compaction and wet granulation processes are known inthe art.

In one embodiment, the tablet shape is prepared by the compactionmethods and apparatus described in issued U.S. Pat. No. 6,767,200.Specifically, the tablet shape is made using a rotary compression moduleincluding a fill zone, compression zone, and ejection zone in a singleapparatus having a double row die construction as shown in FIG. 6therein. The dies of the compression module are preferably filled usingthe assistance of a vacuum, with filters located in or near each die.

The tablet shape may have one of a variety of different shapes. Forexample, the tablet shape may be shaped as a polyhedron, such as a cube,pyramid, prism, or the like; or may have the geometry of a space figurewith some non-flat faces, such as a cone, truncated cone, triangle,cylinder, sphere, torus, or the like. In certain embodiments, a tabletshape has one or more major faces. For example, the tablet shape surfacetypically has opposing upper and lower faces formed by contact with theupper and lower forming tool faces (e.g., die punches) in the compactionmachine. In such embodiments, the tablet shape surface typically furtherincludes a “belly-band” located between the upper and lower faces, andformed by contact with the die walls in the compaction machine. A tabletshape/tablet may also be a multilayer. Applicants have found that sharpedges in the tooling used to make the tablets can cause arcing, and thusmore rounded edges may be needed.

In one embodiment, the method of producing the tablet shape issubstantially free of the use of solvents. In this embodiment, thepowder blend is substantially free of solvents, and the manufacturingprocess (e.g., filling process into the die) is also substantially freeof solvents. Solvents may include, but are not limited to, water,organic solvents such as but not limited to alcohols, chlorinatedsolvents, hexanes, or acetone; or gaseous solvents such as but notlimited to nitrogen, carbon dioxide or supercritical fluids.

In one embodiment a vibratory step is utilized (e.g., added afterfilling of the powder blend but prior to the heating or fusing step, inorder to remove air from the powder blend). In one embodiment avibration with the frequency from about 1 Hz to about 50 KHz is addedwith amplitude from 1 micron to 5 mm peak-to-peak to allow for theflowable powder blend to settle into the cavity of a the die platen(“forming cavity”).

In one embodiment, as shown in FIGS. 1A-1F, a metered volume of powderblend 4 is filled into a Teflon® (or similar electrical and RF energyinsulative material such as ceramic or UHMW plastic) die platen 2. Dieplaten 2 has forming cavity 5 with inner wall 6, upper opening 7 on theupper surface of die platen 2 (which allows powder blend 4 and upperforming tool 1 to move into the forming cavity 5), and lower opening 8on the opposite surface of die platen 2 (which allows powder blend 4 andlower forming tool 3 to move into the forming cavity 5). Powder blend 4may be either gravity fed or mechanically fed from a feeder (not shown).A metallic, electrically conductive lower forming tool 3 is insertedinto the die platen to retain the powder blend 4, within die platen 2. Asimilar metallic, electrically conductive upper forming tool 1 ispositioned above the die platen 2 as shown in FIG. 1B. The forming tools1 and 3, die platen 2, and powder blend 4 are then moved to a compactionand RF heating station as shown in FIG. 1C to form tablet shape 4 a.

This heating station is comprised of an RF generator 7 which producesthe necessary high voltage, high frequency energy. The generator 7 iselectrically connected to movable upper RF electrode plate 8 and movablelower RF electrode plate 6. As shown in FIG. 1C, at this position, thepowder blend 4 is compacted between an upper forming tool 1 and a lowerforming tool 3 by pressure exerted by upper RF electrode plate 8 andlower electrode plate 6 to form tablet shape 4a. Tablet shape 4 a isthen exposed to RF energy from RF generator 7, which heats thewater-containing compound within tablet shape 4 a. After the RF energyis switched off, tablet shape 4 a cools to form the tablet 4 b. In oneembodiment, as shown in FIG. 1D, tablet 4 b is pushed by upper formingtool 1 from the die platen 2 into blister 8, which is used to packagetablet 4 b. In an alternative embodiment, as shown in FIG. 1E, tablet 4b is pushed from the die platen 2 by the lower forming tool 3 and guidedto an ejection chute by a stationary “take-off” bar (not shown). FIG. 1Fshows a 3 dimensional representation of the forming tools 1 and 4, dieplaten 2, and tablet 4 b.

In FIGS. 2A-2H, an alternate embodiment of the invention is shown wherea multilayer tablet is produced. First, powder blend 10 is filled intodie platen 2 as shown in FIG. 2A. Powder blend 10 is tamped or moveddown into die platen 2 by upper forming tool 1 as shown in FIG. 2B toform tablet shape 10 a. Then, powder blend 11 is then filled on top oftablet shape 10 a. The forming tools 1 and 3, die platen 2, tablet shape10 a and powder blend 11 are then moved to the compaction and RF heatingstation as shown in FIG. 2E. RF heating is accomplished as describedabove in FIG. 1C to produce multilayer tablet 12 as shown in FIGS. 2Fand 2G. While a bi-layer tablet is shown in the drawing, additionalmultiple layers can be produced by adding additional powder blends todie platen 2.

FIGS. 3A-3G show another embodiment of the invention where preformedinserts 30 and 31 are inserted into tablet shape 20 a as shown in FIGS.3A-3D. Forming tools 1 and 3, die platen 2, tablet shape 20, andpreformed inserts 30 and 31 are then moved to the compaction and RFheating station as shown in FIG. 3E. RF heating is accomplished asdescribed above in FIG. 1C to produce a multi-component tablet 40 shownin FIGS. 2F and 2G.

FIGS. 4A and 4B show two views of a rotary indexing machine 195 which isdesigned to create large quantities of tablets. In particular, theconfiguration of the apparatus shown is designed to manufacture fragiletablets with minimized risk of damaging them as they are moved throughthe various manufacturing steps. This embodiment of the invention iscomprised of an indexing table 170 having four sets of die platens 175each having sixteen cavities, powder feeder 100, RF generator 150, amachine frame 140, moving RF electrode assemblies 120 and 130, lowerforming tool assembly 110, upper forming tool assembly 210, tabletejection station 160, indexer drive system 180, blister package web 190,and blister lid material roll 191.

FIG. 5A is a top view of the apparatus in the dwell position. FIG. 5B isa top view of the apparatus as the indexing table 170 rotates betweenstations in direction “A”. FIG. 6A depicts a section view through thelower forming tool assembly 110 in a start position of the manufacturingcycle. The lower forming tools 111, which are made of an electricallyconductive metallic material such as brass or stainless steel, areretained in retainer plate 112 (e.g., made of aluminum or steel). Heatedblock 117 is attached to the retainer plate 112 and contains fluidpassages 117 b. Heated (or optionally cooling) fluid is circulatedthrough the heated block 117 by connections to flexible hoses 119 a and119 b which form a supply and return circuit. Heating can also beaccomplished by electric cartridge heaters or other suitable means (notshown). Attached to the retainer plate are cam-follower 114 and linearbearing 113. A guide shaft 116 is fixed to indexing table 170. Theretainer plate and forming tools 111 and are moveable up or downaccording to the profile of barrel cam 115 which cam follower 114 rollsupon. Also shown is die platen 171, which is made of electrical and RFenergy insulative material such as Teflon, UHMW, or ceramic. This isnecessary to prevent a short circuit when the electrically conductiveforming tools are positioned in the RF electric field in subsequentsteps. The forming cavity 171 a is shown empty at this stage of theprocess.

FIG. 6B depicts a section through the powder feeder station 100 of theapparatus. In this station powdered powder blend 101 is gravity fed intodie platen 171. Movable cam segment 118 is adjusted up or down indirection “B” to vary the volume of the forming cavity 171 a by changingthe amount that the lower forming tools 111 penetrate into the dieplaten 171. This adjustable volume feature enables the precise dose ofpowdered powder blend to be selected for a desired tablet weight. Whenthe machine indexes out of the powder feeder station, the rim of feeder102 scrapes against the die platen 171 to create a level powder surfacerelative to the surface of the die platen 171.

FIG. 7 is a section view through the RF station of the apparatus. The RFgenerator 150 is depicted symbolically here. In one embodiment, theconfiguration of the RF generator 150 is a free running oscillatorsystem. It is typically composed of a power vacuum tube (such as atriode), a DC voltage source between 1000 and 8000 volts connectedacross the cathode and plate (anode). A tank circuit is used to impose asinusoidal signal upon the control grid and electrodes thereby producingthe necessary frequency (typically 13.56 MHZ or 27.12 MHZ) and highvoltage field. An example of such RF generator 150 is the COSMOS ModelC10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.). Inanother embodiment, RF energy can be provided by a 50 Ohm systemcomposed of a waveform generator which feeds a radio frequency signal topower amplifiers which are coupled to the electrodes and the load by animpedance matching network.

In FIG. 7, a lower movable RF electrode 121 is shown, movable indirection “D”. It is represented in its down position. The linearmovement is generated by linear actuators which are typically devisessuch as air cylinders or servo motors. Two air cylinders are depicted inFIG. 7. Air cylinder bodies 141 and 142 apply pressure to guide rods 144and 143. Moving platens 132 and 122 are connected to the guide rods andprovide an electrically isolated mounting for electrode plates 131 and121. RF generator 150 connects to the electrode plates 131 and 121through wires 185 and 184. A movable upper RF electrode assembly 130,movable in direction “C”, is shown in its up position. Upper formingtools 133, retainer plate 134, and heated block 135 are all attached tothe movable RF electrode plate 131 and, consequently, move up and downwith it. Powder blend 101 is within die platen 171.

FIG. 8 is a section through the same RF station but shows the RFelectrodes 131 and 121 pressing against the respective forming toolassemblies 133 and 111 to both compact and apply RF energy to powderblend 101 creating tablet 101 a. After application of the RF energy isstopped, the moveable RF electrode plates retract, and the indexingplate 170, die platen 171, and lower forming tool assembly 110 areindexed to the next station.

FIG. 9 is a section view through the tablet ejection station 160.Ejector pins 161 are attached to movable plate 162 (movable in the “E”direction), which is actuated by actuator assembly 163 (for example,this can be a linear servo motor or air cylinder or other suitableactuator). Actuator rod 166 connects to the movable plate 162. Linearbearing 164 and guide rod 165 provide rigidity and support for theactuator plate 162 and prevent destructive side loads created by theejection force from acting upon actuator 163. A blister package 190 isshown below die platen 171.

FIG. 10 is a section through the same assembly after the ejector pins161 have pushed finished tablets 101 a through the die platen 171. Thisdirect placement of tablet into blister helps prevent breakage thatcould occur while using typical means such as feeders or by dumpingtablets into transport drums.

In one embodiment, a lubricant is added to forming cavity prior to theaddition of the flowable powder blend. This lubricant may be a liquid orsolid. Suitable lubricants include but are not limited to solidlubricants such as magnesium stearate, starch, calcium stearate,aluminum stearate and stearic acid; or liquid lubricants such as but notlimited to simethicone, lecithin, vegetable oil, olive oil, or mineraloil. In certain embodiments, the lubricant is added at a percentage byweight of the tablet of less than 5 percent, e.g. less than 2 percent,e.g. less than 0.5 percent. In certain embodiments, the presence of ahydrophobic lubricant can disadvantageously compromise thedisintegration or dissolution properties of a tablet. In one embodimentthe tablet is substantially free of a hydrophobic lubricant. Hydrophobiclubricants include magnesium stearate, calcium stearate and aluminumstearate.

Heating of Tablet Shape to Form Tablet

Various forms of energy may be used in the process to heat thewater-containing compound. Suitable sources of energy include but arenot limited to convection, radio frequency, microwave, UV light,infrared, induction, laser light, and ultrasonic sound. In oneembodiment, radiofrequency energy is used. Radiofrequency heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 1 MHz to about 100 MHz. In one embodiment of the presentinvention, the RF-energy is within the range of frequencies from about 1MHz to about 100 MHz (e.g., from about 5 MHz to 50 MHz, such as fromabout 10 MHz to about 30 MHz). RF energy generators are well known inthe art. Examples of suitable RF generators include, but are not limitedto, COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation,Farmingdale, N.Y.).

The energy (e.g., RF energy) is used to heat the water-containingcompound. The degree of compaction, the type and amount ofwater-containing compound, and the amount of energy used can determinethe hardness and/or type of tablet whether an oral disintegrating tabletor a soft chewable tablet is manufactured.

In one embodiment when RF energy is used, the upper and lower formingtools serve as the electrodes (e.g., they are operably associated withthe RF energy source) through which the RF energy is delivered to thetablet shape. In one embodiment, there is direct contact between atleast one RF electrode (e.g., forming tool) and the tablet shape. Inanother embodiment, there is no contact between any of the RF electrode(e.g., forming tools) and the tablet shape. In one embodiment, the RFelectrodes are in direct contact with the surface of the tablet shapewhen the RF energy is added. In another embodiment, the RF electrodesare not in contact (e.g., from about 1 mm to about 1 cm from the surfaceof the tablet shape) during the addition of the RF energy.

In one embodiment, the RF energy is delivered while the tablet shape isbeing formed. In one embodiment, the RF energy is delivered once thetablet shape is formed. In one embodiment, the RF energy is deliveredafter the tablet shape has been removed from the die.

In one embodiment, the RF energy is applied for a sufficient time toheat substantially all (e.g., at least 90%, such as at least 95%, suchas all) of the water-containing material within said tablet shape aboveits dehydration temperature. In one embodiment, the RF energy is appliedfor a sufficient time to heat only a portion (e.g., less than 75%, suchas less than 50%, such as less than 25%) of the water-containingmaterial within the tablet shape, for example only on a portion of thetablet shape, such as the outside of the tablet shape.

In alternate embodiments of the invention, the forming tools can beconstructed to achieve localized heating effects and can also beconfigured to shape the electric field that is developed across thetools. FIG. 11A shows one such configuration. An RF generator 200 isconnected to RF electrode plates 201 and 202. Forming tools 205 and 204are constructed of an electrically conductive material and they have anattachment 207 and 208 which are made of electrical and RF energyinsulative material such as ceramic, Teflon®, polyethylene, or highdensity polyethylene. Die platen 203 is also constructed of electricaland RF energy insulative material. This configuration creates greaterdistance between the conductive forming tools to weaken the electricfield which is beneficial for producing thin tablets without the risk ofan electric arc forming which would damage the product and tooling. FIG.11B depicts a similar configuration but with forming tools 210 and 211that, respectively, have a recess containing insert 213 and 212 whichare made of electrical and RF energy insulative material. This geometrywill produce a tablet with lesser heating in the area where the inserts213 and 212 are located since the electric field is weaker due to thegreater distance between the conductive portions of 211 and 210. FIG.11C is similar to FIG. 11B only the geometry is reversed so the tabletformed by this configuration will have a greater heating effect at thecenter since the inserts 216 and 217 are at the periphery of respectiveforming tools 214 and 215. FIG. 11D depicts another embodiment wherebythe die platen is constructed of an electrically conductive component221 and electrically insulating component 222, which is made ofelectrical and RF energy insulative material. Forming tools 219 and 218are electrically conductive, but forming tool 218 further containssecond electrically insulating component 220 around the surface of upperforming tool 218 which contact tablet shape 206. This configurationcreates an electric field and associated zones of heating that ispreferential to the conductive portions of the die platen.

FIG. 12A is similar to FIG. 11D except the die platen 233 in thisembodiment is constructed entirely of electrically conductive material.FIGS. 12B and 12C depict two embodiments where the die platen comprisesa respective center portion 245 and 254 that are electrically conductiveand respective outer portions 244/246 and 252/253 is are made ofelectrical and RF energy insulative material. FIG. 12B further includesinsulating component 220 around the surface of lower forming tool 219.FIG. 12D is a further embodiment where the forming tools 263 and 262 aremade of electrical and RF energy insulative material. The die platenportions 264 and 265 are made of electrical and RF energy insulativematerial, but there are two respective electrically conductive portions267 and 266 which are attached to the RF generator circuit 200. In thisconfiguration, the electric field is applied in the horizontal directionacross the tablet shape 206.

As described above, the distance between conductive portions of theforming tool has a strong effect on field strength and heating effect.To create a tablet with uniform heating and texture, a forming tool thatis constructed with equidistant spacing is desirable. FIGS. 13A and 13Bdepict such a configuration. In this embodiment, a wave-shaped formingtools 270 and 273 are shown to create a tablet 272 within die platen 271with a unique appearance. The profiles of the forming tool surfaces areequidistant as shown by dimension “X”.

FIG. 14 is an embodiment wherein a non-uniform heating is used tomanufacture tablet 282. In this embodiment, a tablet with hard and softzones is created. The forming tools 280 and 281 are made withprotrusions at the surface that create high field strength (resulting ingreater heating) where they are closest together (shown by the dimension“Z”) and weaker field strength (resulting in lesser heating) where theyare further apart (shown by the dimension “Y”).

In one embodiment, to help reduce sticking, the tablet is cooled withinthe forming cavity to cool and/or solidify the binder. The cooling canbe passive cooling (e.g., at room temperature) or active cooling (e.g.,coolant recirculation cooling). When coolant recirculation cooling isused, the coolant can optionally circulate through channels inside theforming tools (e.g., punches or punch platen) and/or die or die platen(e.g., as discussed above in FIGS. 6A and 6B). In one embodiment, theprocess uses a die platen having multiple die cavities and upper andlower punch platens having multiple upper and lower punched forsimultaneous forming of a plurality of tablets wherein the platens areactively cooled.

In one embodiment, there is a single powder blend forming the tabletshape which is then heated with the RF energy. In another embodiment,the tablet is formed of at least two different powder blends, at leastone powder blend being RF-curable and at least one formulation being notRF-curable. When cured with RF energy, such tablet shape develops two ormore dissimilarly cured zones. In one embodiment, the outside area ofthe tablet shape is cured, while the middle of the tablet shape is notcured. By adjusting the focus of the RF heating and shape of the RFelectrodes, the heat delivered to the tablet shape can be focused tocreate customized softer or harder areas on the finished tablet.

In one embodiment the RF energy is combined with a second source of heatincluding but not limited to infrared, induction, or convection heating.In one embodiment, the addition of the second source of heat isparticularly useful with a secondary non-RF-meltable binder present inthe powder blend.

In one embodiment, the powder blend is sealed within a chamber duringthe step with which the energy is applied, so that the water iscontained and can be distributed throughout the powder blend. In oneversion of this embodiment, the sealed chamber consists of a die, and atleast one heat source (e.g., RF applying electrode). In one embodiment,upon opening of the sealed chamber, the fused tablet is further dried inorder to allow for the water to escape. This drying step may be achievedusing the energy source or another source of heat.

In one embodiment, microwave energy is used (e.g., in place ofradiofrequency energy) to manufacture the tablet. Microwave heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 100 MHz to about 300 GHz. In one embodiment of the presentinvention, the RF-energy is within the range of frequencies from about500 MHz to about 100 GHz (e.g., from about 1 GHz to 50 GHz, such as fromabout 1 GHz to about 10 GHz). The microwave energy is used to heat thewater-containing material. In such an embodiment, a microwave energysource and microwave electrodes are used in the machine used tomanufacture the tablet.

Inserts within Tablet Shape

In one embodiment, an insert is incorporated into the tablet shapebefore the energy is delivered. Examples include solid compressed formsor beads filled with a liquid composition. Such incorporation of aninsert is depicted in FIGS. 3A-3G.

In one embodiment the pharmaceutically active agent is in the form of agel bead, which is liquid filled or semi-solid filled. The gel bead(s)are added as a portion of the powder blend. In one embodiment, thetablet of this invention has the added advantage of not using a strongcompaction step, allowing for the use of liquid or semisolid filledparticles or beads which are deformable since they will not rupturefollowing the reduced pressure compaction step. These bead walls maycontain gelling substances such as: gelatin; gellan gum; xanthan gum;agar; locust bean gum; carrageenan; polymers or polysaccharides such asbut not limited to sodium alginate, calcium alginate, hypromellose,hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches.The bead walls may further contain a plasticizer such as glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate andtributyl citrate. The pharmaceutically active agent may be dissolved,suspended or dispersed in a filler material such as but not limited tohigh fructose corn syrup, sugars, glycerin, polyethylene glycol,propylene glycol, or oils such as but not limited to vegetable oil,olive oil, or mineral oil. In one embodiment when RF energy is used, theinsert is substantially free of RF-absorbing ingredients, in which caseapplication of the RF energy results in no significant heating of theinsert itself. In other embodiments, the insert contains ingredients andare heated upon exposure to RF energy and, thus, such inserts can beused to soften or melt the water-containing material and/or meltablebinder.

Multi-Layer Tablet

In certain embodiments, the tablet includes at least two layers, e.g.,with different types and/or concentrations of water-containing materialand/or other ingredients or different concentrations of pharmaceuticallyactive agents. Such an embodiment is shown in FIGS. 2A-2D. In oneembodiment, the tablet includes two layers, one layer having orallydisintegrating properties and another layer being chewable orswallowable. In one embodiment, one layer has a water-containingmaterial and another layer does not have a water-containing material. Inone embodiment one layer is compacted at higher compaction force versusthe other layer. In one embodiment, both layers contain same amount ofthe water-containing material, but have different amount ofpharmaceutically active agents and/or other excipients. In oneembodiment, all properties of the two layers are identical but thecolors of the two layers are different.

Effervescent Couple

In one embodiment, the powder blend further contains one or moreeffervescent couples. In one embodiment, effervescent couple containsone member from the group consisting of sodium bicarbonate, potassiumbicarbonate, calcium carbonate, magnesium carbonate, and sodiumcarbonate, and one member selected from the group consisting of citricacid, malic acid, fumaric acid, tartaric acid, phosphoric acid, andalginic acid.

In one embodiment, the combined amount of the effervescent couple(s) inthe powder blend/tablet is from about 2 to about 20 percent by weight,such as from about 2 to about 10 percent by weight of the total weightof the powder blend/tablet.

Orally Disintegrating Tablet

In one embodiment, the tablet is designed to disintegrate in the mouthwhen placed on the tongue in less than about 60 seconds, e.g. less thanabout 45 seconds, e.g. less than about 30 seconds, e.g. less than about15 seconds.

In one embodiment, the tablet meets the criteria for OrallyDisintegrating Tablets (ODTs) as defined by the draft Food and DrugAdministration guidance, as published in April, 2007. In one embodiment,the tablet meets a two-fold definition for orally disintegrating tabletsincluding the following criteria: 1) that the solid tablet is one whichcontains medicinal substances and which disintegrates rapidly, usuallywithin a matter of seconds, when placed upon the tongue and 2) beconsidered a solid oral preparation that disintegrates rapidly in theoral cavity, with an in vitro disintegration time of approximately 30seconds or less, when based on the United States Pharmacopeia (USP)disintegration test method for the specific medicinal substance orsubstances.

Additional Edible Portion

In one embodiment, the tablet is contained next to another edible form.In one embodiment, this edible form is a hard candy or compressed ringthat holds the powder blend during compaction and/or the heating step.

In one embodiment, the outer hard candy form may be made using uniplastrolling or roping and subsequent cutting and stamping, as well asdepositing into molds. The hard candy portion contains one or moresugars selected from the group consisting of isomalt, sucrose, dextrose,corn syrup, lactitol, and lycasin. In one embodiment, the hard candyportion contains at least 50% (such as at least 75%, such as at least90%) by weight of such sugar(s).

In one embodiment, the outer edible form contains a pharmaceuticallyactive agent and the inner tablet contains a second portion of the samepharmaceutically active agent that is in the outer edible form. In oneembodiment, the outer edible form contains a pharmaceutically activeagent and the inner tablet contains a different pharmaceutically activeagent than that in the outer edible form. In one embodiment, the outeredible form disintegrates at a rate of at least 10 times, such as atleast 20 times, the rate of the inner tablet. The first and secondportions can be the same or different.

In one embodiment, the tablet having an outer edible form and an innertablet is coated with an immediate release sugar coating or filmcoating. In one embodiment, to produce such a tablet, the step followingthe fusing (heating) and subsequent cooling of the tablet would involvefurther sugar or film coating in a coating pan.

Hardness/Density of Tablet Shape/Tablet

In one embodiment, the tablet is prepared such that the tablet isrelatively soft (e.g., capable of disintegrating in the mouth or beingchewed). In one embodiment, the hardness of the tablet is preferablyless than about 3 kiloponds per square centimeter (kp/cm²) (e.g., lessthan about 2 kp/cm², such as less than about 1 kp/cm²).

Hardness is a term used in the art to describe the diametral breakingstrength as measured by conventional pharmaceutical hardness testingequipment, such as a Schleuniger Hardness Tester. In order to comparevalues across different size tablets, the breaking strength must benormalized for the area of the break. This normalized value, expressedin kp/cm², is sometimes referred in the art as tablet tensile strength.A general discussion of tablet hardness testing is found in Leiberman etal., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2.sup.nd ed., MarcelDekker Inc., 1990, pp. 213-217, 327-329.

A more preferred test for hardness of the tablet of the presentinvention relies upon a Texture Analyzer TA-XT2i that is fitted with a 7millimeter diameter flat faced probe and setup to measure and reportcompression force in grams. The probe moves at 0.05 millimeters persecond to a depth of penetration of 2 millimeters. The maximumcompression force is recorded. In one embodiment, the measured forcesrecorded for tablets made in accordance with the present invention areless than 10,000 grams (e.g., less than about 1000 grams, such as lessthan about 700 grams. In one embodiment, the measured forces recordedfor tablets made in accordance with the present invention ranges fromabout 100 grams to about 6000 grams, such as from about 100 grams toabout 1000 grams, such as from about 75 grams to about 700 grams) with adeviation of ±50 grams. In another embodiment the measured forcesrecorded for tablets is less than 700 grams.

In one embodiment, the density of the tablet is less than about 2 g/cc(e.g., less than about 0.9 g/cc, such as less than about 0.8 g/cc, suchas less than about 0.7 g/cc). In one embodiment, the difference in thedensity of the powdered material following the compaction step is lessthan about 40 percent (e.g., less than about 25 percent, such as lessthan about 15 percent).

Tablets Coatings

In one embodiment, the tablet includes an additional outer coating(e.g., a translucent coating such as a clear coating) to help limit thefriability of the tablet. Suitable materials for translucent coatingsinclude, but are not limited to, hypromellose, hydroxypropylcellulose,starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol andpolyethylene glycol mixtures and copolymers, and mixtures thereof.Tablets of the present invention may include a coating from about 0.05to about 10 percent, or about 0.1 to about 3 percent by weight of thetotal tablet.

Surface Treating of the Tablet

In one embodiment, the surface of the tablet shape and/or the tablet isfurther treated with energy (e.g., convection, infrared, or RF energy)to soften or melt the material on the surface of the tablet and thencooled or allowed to cool to further smooth the texture, enhance thegloss of surface of the tablet, limit the friability of the tablet,and/or provide a mark for identification. In one embodiment, the surfaceof the tablet is further exposed to infrared energy wherein the majority(at least 50 percent, such as least 90 percent, such as at least 99percent) of the wavelength of such infrared energy is from about 0.5 toabout 5 micrometers such as from about 0.8 to about 3.5 micrometers(e.g., by use of a wavelength filter). In one embodiment, the infraredenergy source is a quartz lamp with a parabolic reflector (e.g., tointensify the energy) and a filter to remove unwanted frequencies.Examples of such infrared energy sources include the SPOT IR 4150(commercially available from Research, Inc., Eden Prairie, Minn.).

Use of Tablet

The tablets may be used as swallowable, chewable, or orallydisintegrating tablets to administer the pharmaceutically active agent.

In one embodiment, the present invention features a method of treatingan to ailment, the method including orally administering theabove-described tablet wherein the tablet includes an amount of thepharmaceutically active agent effective to treat the ailment. Examplesof such ailments include, but are not limited to, pain (such asheadaches, migraines, sore throat, cramps, back aches and muscle aches),fever, inflammation, upper respiratory disorders (such as cough andcongestion), infections (such as bacterial and viral infections),depression, diabetes, obesity, cardiovascular disorders (such as highcholesterol, triglycerides, and blood pressure), gastrointestinaldisorders (such as nausea, diarrhea, irritable bowel syndrome and gas),sleep disorders, osteoporosis, and nicotine dependence.

In one embodiment, the method is for the treatment of an upperrespiratory disorder, wherein the pharmaceutically active agent isselected from the group of phenylephrine, cetirizine, loratadine,fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine,chlophedianol, and pseudoephedrine.

In this embodiment, the “unit dose” is typically accompanied by dosingdirections, which instruct the patient to take an amount of thepharmaceutically active agent that may be a multiple of the unit dosedepending on, e.g., the age or weight of the patient. Typically the unitdose volume will contain an amount of pharmaceutically active agent thatis therapeutically effective for the smallest patient. For example,suitable unit dose volumes may include one tablet.

EXAMPLES

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples.

Example 1 Manufacture of Powder Blend Containing Acetaminophen

The acetaminophen powder blend for an orally disintegrating tablet,containing the ingredients of Table 1, is manufactured as follows:

TABLE 1 Coated Acetaminophen Powder Blend Formulation Ingredient G/BatchMg/Tablet Dextrose Monohydrate 6.14 552.78 Maltodextrin 0.6 54 SucraloseNF 0.06 5.4 D&C Yellow #10 Al Lake 0.01 0.54 Coated Acetaminophen (91%)*1.94 174.78 Peppermint 0.1 9 Disodium H Phosphate 0.75 67.5Dodecahydrate USP** Polyethylene Oxide NF 0.4 36 Total 10 900*Commercially Available from Eurand in Vidalia, OH **Na₂HPO₄•7H₂O-Commercially available from the Dow Corporation in Midland, MIEach ingredient is screened through a 30 mesh screen, placed togetherinto a 500 cc plastic bottle, and mixed end-over-end for 5 minutes.

Example 2 Manufacture of Orally Disintegrating Tablet ContainingAcetaminophen

A portion of the powder blend from Example 1 is placed into a ½ inchdiameter forming cavity of an electrically insulative Teflon die platen.The powder blend is then tamped between an upper and lower flat-facedmetal forming tools into a shape conformal to the surface of the formingtools. The tamping pressure is typically between 10 and approximately 50psi of pressure. The forming tools, die platen and tablet shape are thenplaced between the upper RF electrode and lower RF electrode powered byan RF heating unit using a COSMOS Model C10X16G4 (Cosmos ElectronicMachine Corporation, Farmingdale, N.Y.) RF generator having an output of4 KW of power, frequency of 27 MHz, and the vacuum capacitor is set at140. The forming tools are heated with reciculating water at atemperature of 57° C. The upper RF electrode is brought into contactwith the upper forming tool and the lower RF electrode is brought intocontact with lower forming tool. The RF heating unit is energized for 2to 5 seconds. The resulting tablet is then ejected from the die platenusing the lower forming tool.

Example 3 Preparation of Outer Edible Ring with Fused OrallyDisintegrating Tablet Inner Portion (a) Preparation of an Edible OuterRing Portion

All materials set forth in Table 2 below are manually passed through a30 mesh screen. One and a half (1.5) kg of the resulting blend are thenplaced in a 4 quart V-Blender and mixed for 5 minutes.

TABLE 2 Weight Percent Ingredients (w/w) Weight (mg) Sorbitol 5 50Compressible Sucrose* 92.75 927.5 Menthol 1 10 Peppermint Flavor 0.5 5Magnesium Stearate 0.75 7.5 TOTAL 100 1000 *Commercially available fromDomino Specialty Ingredients, Baltimore, MD

Four hundred grams (400 g) of the resulting blend is then removed fromthe blender and compressed on a rotary tablet press at 60 rpm using ¾″ringed tablet tooling in order to yield flat faced rings having ½″ emptycenters having a weight of 1000 mg, a hardness range of not less than 15kp/cm², and a thickness of about 0.20 inches.

(b) Preparation of Orally Disintegrating Tablet Inner Portion

An orally disintegrating immediate release loratadine powder blendformulation including the ingredients of Table 3 is manufactured asfollows:

TABLE 3 Granulation Blend G/Batch Mg/Tablet Dextrose 86.67 433.3Monohydrate Sodium Hydrogen 9.62 48.1 Phosphate Hydrate Sucralose USP0.6 3 Flavor 1.12 5.6 Loratadine 2 10 Total 100 500

Dextrose Monohydrate, sucralose and flavor are screened through a 30mesh screen and placed into a 500 cc plastic bottle and mixedend-over-end for 5 minutes. The loratadine and sodium hydrogen phosphatehydrate are added and blended end over end for an additional 3 minutes.

(c): Preparation of Outer Edible Ring with Fused Orally DisintegratingTablet Inner Portion

The resulting powder blend from part (b) is then removed from theblender. The edible outer ring portions from part (a) are individuallyplaced into the forming cavity of a die platen as set forth in Example2. The powder blend from part (b) is then placed in the center portionof the ring portions and gently tamped at 100 pounds in order to yield adosage form and having a total weight of 1500 mg. The upper forming toolis then positioned at a distance of approximately 1 cm above the surfaceof the dosage form, and the RF electrodes are then energized for 2 to 5seconds as set forth in Example 2. The resulting tablet is then ejectedfrom the die platen using the lower forming tool.

It is understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

1. A process for making a tablet comprising compacting a powder blend ina die platen to form a tablet shape, wherein said powder blend comprisesa pharmaceutically active agent and a water-containing material, andapplying energy to said tablet shape for a sufficient period of time toheat the water-containing material within said tablet shape above itsdehydration temperature to form said tablet.
 2. A process of claim 1,wherein said energy is radiofrequency energy.
 3. The process of claim 1,wherein said powder blend further comprises one or more carbohydrates.4. The process of claim 1, wherein said powder blend comprises fromabout 0.01 to about 30 percent, by weight, of said pharmaceuticallyactive agent and from about 1 to about 30 percent, by weight, of saidwater-containing material.
 5. The process of claim 3, wherein saidpowder blend comprises from about 0.01 to about 30 percent, by weight,of said pharmaceutically active agent, from about 1 to about 30 percent,by weight, of said water-containing material, and from about 30 to about95 percent, by weight, of said one or more carbohydrates.
 6. The processof claim 1, wherein said water-containing material is a hydrate salt. 7.The process of claim 3, wherein said one or more carbohydrates areselected from the group consisting of dextrose monohydrate, mannitol,erythritol, dextrose, lactose, sorbitol, isomalt, sucrose, dextrates andmaltodextrins.
 8. The process of claim 1, wherein said radiofrequencyenergy is applied to said tablet shape within said die platen.
 9. Theprocess of claim 1, wherein said powder blend is compacted with a forceless than 0.3 kiloNewtons.
 10. The process of claim 1, wherein saidradiofrequency energy has a frequency of from about 1 MHz to 100 MHz.11. The process of claim 1, wherein said powder blend has an averageparticle size of less than 500 microns.
 12. The process of claim 1,wherein said tablet disintegrates in the mouth when placed on the tonguein less than about 30 seconds.
 13. The process of claim 1, wherein saidtablet meets the criteria for orally disintegrating tablets as definedby the draft Food & Drug Administration guidance, as published April,2007.
 14. The process of claim 1, wherein said tablet has a hardness ofless than 700 grams as measure using Texture Analyzer TA-XT2i that isfitted with a 7 millimeter diameter flat faced probe.
 15. The process ofclaim 1, wherein said tablet has a density less than 0.8 g/cc.
 16. Theprocess of claim 1, wherein said process comprises the steps of: (i)introducing said powder blend into a forming cavity within said dieplaten; (ii) compacting said powder blend by introducing at least oneforming tool into said die platen with sufficient force such that atablet shape is formed; (iii) applying said energy to said tablet shape,within said forming cavity to form said tablet; and (iv) removing saidtablet from said forming cavity.
 17. The process of claim 4, whereinsaid process further comprises the step of cooling said tablet in saiddie prior to removing said tablet from said die.
 18. The process ofclaim 2, wherein said energy is radiofrequency energy and at least onesaid forming tool emits said radiofrequency energy to said tablet shape.19. The process of claim 2, wherein said energy is radiofrequency energyand the die platen emits said radiofrequency energy to said tabletshape.
 20. The process of claim 1, wherein said energy is radiofrequencyenergy and said powder blend is compacted using an upper forming tooland a lower forming tool, and at least one of said upper forming tool orlower forming tool emits said radiofrequency energy to said tabletshape.
 21. The process of claim 1, wherein the surface of said tablet isfurther exposed to infrared energy wherein the majority of thewavelength of said infrared energy from about 0.5 to about 5micrometers.
 22. A tablet manufactured according to the process of claim1.